Many current medicines suffer from poor absorption, distribution, metabolism and/or excretion (ADME) properties that prevent their wider use. Poor ADME properties are also a major reason for the failure of drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve certain ADME properties, these approaches fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high plasma level of drug. This, however, introduces a number of potential treatment problems such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment.
In some select cases, a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection. These drugs are typically co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism. Ritonavir causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs. Similarly, quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism in a treatment of pseudobulbar affect. Quinidine, however, is a CYP2D6 inhibitor that has unwanted side effects that greatly limit its use in potential combination therapy.
In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance. The inhibition of a CYP enzyme's activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. This can cause those other drugs to accumulate in the body to toxic levels.
A potentially attractive strategy for improving a drug's metabolic properties is deuterium modification. In this approach, one attempts to slow the CYP-mediated metabolism of a drug by replacing one or more hydrogen atoms with deuterium atoms. Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Deuterium forms stronger bonds with carbon than hydrogen does. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and tolerability. At the same time, because the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
Over the past 35 years, the effects of deuterium substitution on the rate of metabolism have been reported for a very small percentage of approved drugs (see, e.g., Blake, M I et al., J Pharm Sci, 1975, 64:367-91; Foster, A B, Adv Drug Res, 1985, 14:1-40 (“Foster”); Kushner, D J et al., Can J Physiol Pharmacol, 1999, 79-88; Fisher, M B et al., Curr Opin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results have been variable and unpredictable. For some compounds deuteration caused decreased metabolic clearance in vivo. For others, there was no change in metabolism. Still others demonstrated increased metabolic clearance. The variability in deuterium effects has also led experts to question or dismiss deuterium modification as a viable drug design strategy for inhibiting adverse metabolism. (See Foster at p. 35 and Fisher at p. 101).
The effects of deuterium modification on a drug's metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism. Only by actually preparing and testing a deuterated drug can one determine if and how the rate of metabolism will differ from that of its undeuterated counterpart. See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, will be different for each drug.
GABAA receptors are ligand-gated chloride channels that mediate the inhibitory effects of γ-aminobutyric acid (GABA) in the central nervous system. GABAA receptors are heteromeric proteins of five subunits primarily found as receptors containing α, β, and γ subunits in a 2:2:1 stoichiometry. GABAA receptors containing the α1, α2, α3, or α5 subunits contain a binding site for benzodiazepines, which is the basis for the pharmacologic activity of benzodiazepines.
NS11394, also known as 3′-[5-(1-hydroxy-1-methylethyl)-1H-benzimidazol-1-yl]biphenyl-2-carbonitrile, is a GABAA receptor modulator. NS11394 has been found to completely reverse inflammatory and neuropathic pain-like behaviors in animal models following oral administration and is well tolerated (Mirza, N. et al., 38th annual meeting of the Society for NeuroScience in Washington D.C., Nov. 15-19, 2008, Abst 531.26). It has also been shown that NS11394 is potent and highly effective in rodent anxiety models, and that the compound's anxiolytic efficacy is most likely mediated through its high efficacy at GABAA α3 receptors (Mirza, N. et al., 38th annual meeting of the Society for NeuroScience in Washington D.C., Nov. 15-19, 2008, Abst 762.2). Similar results have been presented by Munro, G. et al. at the Taking the Pain Out of Drug Discovery 2009 Meeting in London, UK (Mar. 26, 2009) and by Erichsen, H. K. et al., 12th World Congr Pain (Aug. 17-22, Glasgow) 2008, Abst PH 244. No dependence issues were observed in this study.
The GABA subtype selectivity for NS11394 is in the order α5>α3>α2>α1. Indications for which NS 11394 is useful include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, and generalized or substance-induced anxiety disorder; stress disorders including post-traumatic and acute stress disorder; sleep disorders; memory disorder; neuroses; convulsive disorders, for example epilepsy, seizures, convulsions, or febrile convulsions in children; migraine; mood disorders; depressive or bipolar disorders, for example depression, single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders, including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; pain and nociception, e.g. neuropathic pain and inflammatory pain; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation; motion sickness, post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; neuralgia, e.g. trigeminal neuralgia; muscle spasm or spasticity, e.g. in paraplegic patients; the effects of substance abuse or dependency, including alcohol withdrawal; cognitive disorders, such as Alzheimer's disease; cerebral ischemia, stroke, head trauma; tinnitus; disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work; diabetes, type 1 diabetes (insulin-dependent diabetes mellitus), type 2 diabetes, hyperinsulinemia; and other inflammatory diseases and auto immune disorders. Other indications are described in patent publication WO 2007110374.
Despite the purported beneficial activities of NS11394, there is a continuing need for new compounds that have beneficial effects as anxiolytics and antinociceptives without sedative and proconvulsant effects.